Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/ or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as “Caloric Restriction Mimetics” that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.